Carvedilol, the first beta blocker labeled in the United States for the treatment of heart failure, has been shown to improve left ventricular ejection fraction and may reduce mortality. Carvedilol is chemically known as 1-(9H-carbazol-4yloxy)-3-[[2-(2-methoxyphenoxy)-ethyl]amino]-propan-2-ol, which has the following structure (II).

Carvedilol is disclosed in U.S. Pat. No. 4,503,067 to Wiedemann et al. Carvedilol is indicated in the management of congestive heart failure (CHF), as an adjunct to conventional treatments (ACE inhibitors and diuretics). Currently, carvedilol is used for treating patients suffering with hypertension, congestive heart failure and angina. The use of carvedilol has been shown to provide additional morbidity and mortality benefits in CHF (Packer M, Fowler M B, Roecker E B, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106(17):2194-9. PMID 12390947
The patent application publication US20050277689 A1 and U.S. Pat. No. 7,268,156 both describe crystalline forms of carvedilol dihydrogen phosphate including the hemihydrate, the dihydrate and certain solvates thereof. The publications state that the various carvedilol phosphate forms exhibit high aqueous solubility. Carvedilol dihydrogen phosphate hemihydrate is disclosed to be synthesized by reacting carvedilol with phosphoric acid in aqueous acetone. Crystals of the product are obtained by seeding with carvedilol dihydrogen phosphate. The publications state that the corresponding dihydrate is obtained by slurrying the hemihydrate in an acetone/water mixture for several days, or by distilling off the acetone to crystallize the product in the residual solvent.
The PCT patent publication WO2008002683A2 describes amorphous carvedilol phosphate (in which carvedilol and phosphate are defined as being present in a molar ratio of about 3:1), amorphous carvedilol hydrogen phosphate (in which carvedilol and phosphoric acid are defined as being present in a molar ratio of about 2:1), amorphous carvedilol dihydrogen phosphate (in which carvedilol and phosphate are defined as being present in a molar ratio of about 1:1), crystalline carvedilol dihydrogen phosphate as well as numerous exemplary processes for preparation of the same. The different forms of carvedilol dihydrogen phosphate disclosed in WO2008002683A2 are either the hemihydrate or the dihydrate. Methods of synthesizing carvedilol dihydrogen phosphate are disclosed generally as including combining carvedilol, phosphoric acid and an essentially nonaqueous organic solvent, and precipitating carvedilol dihydrogen phosphate from the reaction mixture.
WO2008002683A2 provides characterization data such as x-ray diffraction (XRD), differential scanning calorimetry (DSC) and thermo gravimetric analysis (TGA) for the claimed compounds.
The PCT patent publication WO2007144900A2 claims crystalline carvedilol dihydrogen phosphate sesquihydrate having moisture content between 4 to 7%, preferably to 4.5 to 6.0%. Processes for preparing this composition are disclosed.
There is a need for improved carvedilol compositions displaying high purity, high stability, and high bioavailability in a mammal after oral administration. The latter need includes the need for a composition having high solubility in environments of relatively neutral pH or higher such as may be encountered in the digestive tract of the small intestine of the mammal, where the solubility of carvedilol is low. There further is a need for a pharmaceutical composition including a carvedilol salt that provides rapid dissolution after oral administration, and high bioavailability of active carvedilol.
The present disclosure addresses these and related needs. The presently disclosed composition and methods are directed to provide stable and highly water soluble novel crystalline carvedilol dihydrogen phosphate monohydrate salt of formula I. The invention also directed to convenient, robust and rugged processes for the preparation of the subject matter of the present invention